Abstract The burden of co-morbid HIV and mental illness in South Africa is staggering: 19% percent of South Africans live with HIV, and 14-30% of people living with HIV suffer from common mental disorders. Only 25% receive mental health treatment of any kind. Common mental disorders co-morbid with HIV threaten the effectiveness of HIV treatment and carry damaging stigmas. Integrating care for mental illness into HIV-related services has the potential to address these stigmas, reduce treatment gaps, and improve treatment outcomes. Integrated services are demonstrating effectiveness in South Africa, yet the barriers to and facilitators of successful implementation remain undefined. This multi-disciplinary project benefits from a timely collaboration, rich with many combined years of experience at the intersection of mental health and HIV/AIDS, and applies the methods of implementation science to strengthen the implementation of integrated mental health and HIV- related services in South Africa. This study applies the Consolidated Framework for Implementation Research to identify and explain the intervention- and provider-level barriers and facilitators that are associated with the successful screening and referral of patients by nurses as part of integrated HIV and mental health services in South Africa. It will gain a holistic understanding of the challenges of integration by combining questionnaire and interview data collected from nurses with available secondary data from routine program monitoring. This study builds on the results and resources of three ongoing projects. The DFID-funded Programme for Improving Mental Health Care (PRIME) project and NIH-funded pragmatic cluster randomized controlled Comorbid Affective Disorders, AIDS/HIV, and Long Term Health (COBALT) trial are examining the methods for and impact of integrated mental health and HIV services in a subset of health facilities in two districts in North West Province, South Africa. Simultaneously, a CDC-funded collaboration of the University of Washington, I- TECH South Africa, and the University of KwaZulu-Natal is strengthening these efforts and scaling to two new districts. By leveraging these projects, and triangulating robust quantitative and qualitative data, this study will address key gaps in knowledge about the factors associated with the successful integration of mental health and HIV services. This will be the first study to apply a rigorous framework for implementation science research, including validated measures of predictors of successful implementation, to the investigation of the process of integrating mental health and HIV services in a low-resource setting. Moreover, assessment of these barriers and facilitators will lead directly to refinement of approaches to scale-up in South Africa, improving scale-up and subsequent patient outcomes.